Treatment systems and methods for affecting glands and other targeted structures

ABSTRACT

Treatment systems, methods, and apparatuses for treating acne, hyperhidrosis, and other skin conditions are described. Aspects of the technology can include cooling a surface of a patient&#39;s skin and detecting changes in the tissue. The tissue can be cooled a sufficient length of time and to a temperature low enough to affect glands or other targeted structures in the skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No.15/115,503, filed Jul. 29, 2016, now pending, which is a 35 U.S.C. § 371U.S. National Phase application of International Application No.PCT/US2015/013971, filed Jan. 30, 2015, which claims priority to U.S.Provisional Patent Application No. 61/934,549, filed Jan. 31, 2014,entitled “COMPOSITIONS, TREATMENT SYSTEMS AND METHODS FOR IMPROVEDCOOLING OF LIPID-RICH TISSUE;” U.S. Provisional Patent Application No.61/943,250, filed Feb. 21, 2014, entitled “TREATMENT SYSTEMS, METHODS,AND APPARATUSES FOR IMPROVING THE APPEARANCE OF SKIN;” and U.S.Provisional Patent Application No. 61/943,257, filed Feb. 21, 2014,entitled “TREATMENT SYSTEMS, METHODS AND APPARATUS FOR REDUCING SKINIRREGULARITIES CAUSED BY CELLULITE.” All of these patent applicationsare incorporated herein by reference in their entireties.

INCORPORATION BY REFERENCE OF COMMONLY-OWNED APPLICATIONS AND PATENTS

The following commonly assigned U.S. Patent Applications and U.S.Patents are incorporated herein by reference in their entirety:

U.S. Patent Publication No. 2008/0287839 entitled “METHOD OF ENHANCEDREMOVAL OF HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS AND TREATMENTAPPARATUS HAVING AN ACTUATOR”;

U.S. Pat. No. 6,032,675 entitled “FREEZING METHOD FOR CONTROLLED REMOVALOF FATTY TISSUE BY LIPOSUCTION”;

U.S. Patent Publication No. 2007/0255362 entitled “CRYOPROTECTANT FORUSE WITH A TREATMENT DEVICE FOR IMPROVED COOLING OF SUBCUTANEOUSLIPID-RICH CELLS”;

U.S. Pat. No. 7,854,754 entitled “COOLING DEVICE FOR REMOVING HEAT FROMSUBCUTANEOUS LIPID-RICH CELLS”;

U.S. Patent Publication No. 2011/0066216 entitled “COOLING DEVICE FORREMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS”;

U.S. Patent Publication No. 2008/0077201 entitled “COOLING DEVICES WITHFLEXIBLE SENSORS”;

U.S. Patent Publication No. 2008/0077211 entitled “COOLING DEVICE HAVINGA PLURALITY OF CONTROLLABLE COOLING ELEMENTS TO PROVIDE A PREDETERMINEDCOOLING PROFILE”;

U.S. Patent Publication No. 2009/0118722, filed Oct. 31, 2007, entitled“METHOD AND APPARATUS FOR COOLING SUBCUTANEOUS LIPID-RICH CELLS ORTISSUE”;

U.S. Patent Publication No. 2009/0018624 entitled “LIMITING USE OFDISPOSABLE SYSTEM PATIENT PROTECTION DEVICES”;

U.S. Patent Publication No. 2009/0018623 entitled “SYSTEM FOR TREATINGLIPID-RICH REGIONS”;

U.S. Patent Publication No. 2009/0018625 entitled “MANAGING SYSTEMTEMPERATURE TO REMOVE HEAT FROM LIPID-RICH REGIONS”;

U.S. Patent Publication No. 2009/0018627 entitled “SECURE SYSTEM FORREMOVING HEAT FROM LIPID-RICH REGIONS”;

U.S. Patent Publication No. 2009/0018626 entitled “USER INTERFACES FOR ASYSTEM THAT REMOVES HEAT FROM LIPID-RICH REGIONS”;

U.S. Pat. No. 6,041,787 entitled “USE OF CRYOPROTECTIVE AGENT COMPOUNDSDURING CRYOSURGERY”;

U.S. Pat. No. 8,285,390 entitled “MONITORING THE COOLING OF SUBCUTANEOUSLIPID-RICH CELLS, SUCH AS THE COOLING OF ADIPOSE TISSUE”;

U.S. Provisional Patent Application Ser. No. 60/941,567 entitled“METHODS, APPARATUSES AND SYSTEMS FOR COOLING THE SKIN AND SUBCUTANEOUSTISSUE”;

U.S. Pat. No. 8,275,442 entitled “TREATMENT PLANNING SYSTEMS AND METHODSFOR BODY CONTOURING APPLICATIONS”;

U.S. patent application Ser. No. 12/275,002 entitled “APPARATUS WITHHYDROPHILIC RESERVOIRS FOR COOLING SUBCUTANEOUS LIPID-RICH CELLS”;

U.S. patent application Ser. No. 12/275,014 entitled “APPARATUS WITHHYDROPHOBIC FILTERS FOR REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICHCELLS”;

U.S. Patent Publication No. 2010/0152824 entitled “SYSTEMS AND METHODSWITH INTERRUPT/RESUME CAPABILITIES FOR COOLING SUBCUTANEOUS LIPID-RICHCELLS”;

U.S. Pat. No. 8,192,474 entitled “TISSUE TREATMENT METHODS”;

U.S. Patent Publication No. 2010/0280582 entitled “DEVICE, SYSTEM ANDMETHOD FOR REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS”;

U.S. Patent Publication No. 2012/0022518 entitled “COMBINED MODALITYTREATMENT SYSTEMS, METHODS AND APPARATUS FOR BODY CONTOURINGAPPLICATIONS”;

U.S. Publication No. 2011/0238050 entitled “HOME-USE APPLICATORS FORNON-INVASIVELY REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS VIAPHASE CHANGE COOLANTS, AND ASSOCIATED DEVICES, SYSTEMS AND METHODS”;

U.S. Publication No. 2011/0238051 entitled “HOME-USE APPLICATORS FORNON-INVASIVELY REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS VIAPHASE CHANGE COOLANTS, AND ASSOCIATED DEVICES, SYSTEMS AND METHODS”;

U.S. Publication No. 2012/0239123 entitled “DEVICES, APPLICATION SYSTEMSAND METHODS WITH LOCALIZED HEAT FLUX ZONES FOR REMOVING HEAT FROMSUBCUTANEOUS LIPID-RICH CELLS”;

U.S. patent application Ser. No. 13/830,413 entitled “MULTI-MODALITYTREATMENT SYSTEMS, METHODS AND APPARATUS FOR ALTERING SUBCUTANEOUSLIPID-RICH TISSUE”;

U.S. patent application Ser. No. 13/830,027 entitled “TREATMENT SYSTEMSWITH FLUID MIXING SYSTEMS AND FLUID-COOLED APPLICATORS AND METHODS OFUSING THE SAME”;

U.S. Provisional Patent Application No. 61/943,251 entitled “TREATMENTSYSTEMS AND METHODS FOR TREATING CELLULITE”; and

U.S. Provisional Patent Application No. 61/943,257 entitled “TREATMENTSYSTEMS, METHODS, AND APPARATUS FOR REDUCING IRREGULARITIES CAUSED BYCELLULITE.”

TECHNICAL FIELD

The present disclosure relates generally to treatment systems andmethods for affecting target structures in a subject's body. Inparticular, several embodiments are directed to treatment systems andmethods for affecting glands to treat acne, hyperhidrosis, cysts, orother conditions.

BACKGROUND

Exocrine glands found in the skin have a role in maintaining skin healthincluding lubricating, waterproofing, cleansing and/or cooling the skinor hair follicles of the body by excreting water-based, oily and/or waxysubstances through skin pores or hair follicles. Overproduction and/orover-secretion of these substances by certain exocrine glands, such assebaceous glands and sudoriparous glands (e.g., sweat glands), can causeunappealing skin disorders that have proved to be difficult to treat.For example, overproduction of sebum, a waxy substance produced andsecreted by sebaceous glands, can lead to formation of comedones (e.g.,blackheads, whiteheads, etc.) as well as other inflammatory conditionsof the skin associated with acne (e.g., inflamed papules, pustules,nodules, etc.) and can potentially lead to scarring of the skin.Overproducing sebaceous glands associated with hair follicles can bemostly found in highly visible regions of the body, such as on the face,neck, upper chest, shoulders and back, and demand for effectivetreatments has been and remains quite high.

Hyperhidrosis is a condition associated with excessive sweating andresults from the overproduction and secretion of sweat from sweat glandsin the skin of mammals. Excessive sweating from eccrine sweat glands,which are distributed almost all over the body, can cause discomfort andembarrassment. For example, focal hyperhidrosis can occur on the palmsof the hands, soles of the feet, face and scalp. Apocrine sweat glands,particularly in the axilla (i.e., armpits), have oil-producing cellsthat can contribute to excessive production and undesirable odor.Treatment for these conditions are often ineffective, non-lasting,and/or have undesirable side-effects.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, identical reference numbers identify similar elementsor acts. The sizes and relative positions of elements in the drawingsare not necessarily drawn to scale.

FIG. 1 is a schematic cross-sectional view of the skin, dermis, andsubcutaneous tissue of a subject.

FIG. 2 is a schematic cross-sectional view of the skin, dermis, andsubcutaneous tissue of the subject in FIG. 1 after treating sebaceousglands.

FIG. 3 is a partially schematic, isometric view of a treatment systemfor non-invasively treating targeted structures in a human subjects bodyin accordance with an embodiment of the technology.

FIG. 4 is a cross-sectional view of a conduit of the treatment system ofFIG. 3.

FIG. 5 is a cross-sectional view of a treatment device applied to atreatment site in accordance with an embodiment of the technology.

FIGS. 6A to 6C are schematic cross-sectional views of treatment devicesin accordance with embodiments of the technology.

FIG. 6D is a side view of an applicator for treating discrete featuresin accordance with embodiments of the technology.

FIGS. 6E and 6F are cross-sectional views of a distal end of theapplicator of FIG. 6D.

FIGS. 7 to 10 are flow diagrams illustrating methods for affectingtarget regions in accordance with embodiments of the technology.

FIG. 11 is a schematic block diagram illustrating computing systemsoftware modules and subcomponents of a computing device suitable to beused in treatment systems in accordance with embodiments of thetechnology.

DETAILED DESCRIPTION A. Overview

The present disclosure describes treatment systems and methods foraffecting target structures in tissue. The systems and methods disclosedherein can be used to target glands (e.g., exocrine glands, sebaceousglands, sudoriparous glands, etc.), structures in the skin (e.g., hairfollicles, superficial nerves, etc.), and/or layer(s) of tissue (e.g.,dermal layer, epidermal layer, layer(s) of the epidermis, etc.). Severalof the details set forth below are provided to describe the followingexamples and methods in a manner sufficient to enable a person skilledin the relevant art to practice, make, and use them. Several of thedetails and advantages described below, however, may not be necessary topractice certain examples and methods of the technology. Althoughdescribed examples and methods target glands, the technology can targetother structures or features and may include other examples and methodsthat are within the scope of the technology but are not described indetail. The treatment systems and treatment devices disclosed herein canperform a wide range of cryotherapy procedures.

Reference throughout this specification to “one example,” “an example,”“one embodiment,” or “an embodiment” means that a particular feature,structure, or characteristic described in connection with the example isincluded in at least one example of the present technology. Thus, theoccurrences of the phrases “in one example,” “in an example,” “oneembodiment,” or “an embodiment” in various places throughout thisspecification are not necessarily all referring to the same example.Furthermore, the particular features, structures, routines, blocks,stages, or characteristics may be combined in any suitable manner in oneor more examples of the technology. The headings provided herein are forconvenience only and are not intended to limit or interpret the scope ormeaning of the technology.

Various aspects of the technology are directed to treatment systems andmethods for affecting target structures in a human subject's body. Thetarget structures can be glands, hair follicles, nerves (e.g.,superficial nerves), or one or more layers of tissue (e.g., dermallayer, epidermal layer, layer(s) of the epidermis, etc.). To treat acne,the surface of the subject's skin can be cooled to produce a temperatureat or below 0, 5, 10, 15, or 20 degrees C. and to produce either acooling event or a freeze event in a targeted portion of the skin withsebaceous glands. The skin can be cooled to maintain the cooled state orfrozen state of the targeted portion of the skin for a period of timelong enough to alter a level of secretion production by the sebaceousglands. The characteristics of the cooling event or freeze event can becontrolled to manage thermal injury. Such characteristics include,without limitation, the amount of cooling or freezing, density anddistribution of ice crystals, freezing rate, etc. Cryotherapy canaffect, without limitation, glandular function, structures of glands(e.g., gland portions, duct portions, etc.), number of glands, and/orsizes of glands.

Freeze events can include partially or completely freezing liquids orlipids proximate to or within glands to destroy, reduce, disrupt,modify, or otherwise affect glands or the supporting anatomical features(e.g., ducts, pores, hair follicles, etc.). In some embodiments, totreat exocrine glands, a subject's skin can be cooled to produce apartial freeze event in a portion of skin with exocrine glands. Thelevel of freezing can be controlled to limit tissue damage, such astissue damage to non-targeted tissue, damage of targeted tissue (e.g.,to avoid excess damage to targeted tissue), and so forth. The subject'sskin can be continuously or periodically cooled/heated to adjust thelevel of freezing. For example, the skin surface can be cooled or heatedto increase or decrease, respectively, the number and/or sizes of icecrystals at the target region.

In some embodiments, a method comprises cooling a subject's skin toproduce a cooling event in the skin, but not a freeze event. After thecooling event begins, the subject's skin is cooled to maintain thecooling event to alter glands (e.g., gland function, gland size, glandstructure, gland number, etc.). The cooling event can alternatively be afreeze event that involves at least partially or totally freezing atarget region with the glands so as to alter secretion levels of theglands. In acne treatments, the freeze event can injure sebaceous glandsto reduce sebum production. In hyperhidrosis treatments, the freezeevent can injure sweat glands to reduce sweating. The location andcharacteristics of the freeze event can be selected based on treatmentsto be performed.

Aspects of the technology can include a method for treating a subject'sexocrine glands by cooling a surface of a subject's skin with a coolingdevice to produce a partial or total freeze event in a portion of theskin with exocrine glands. The partial or total freeze event in thepatient's skin can be detected. The cooling device and other treatmentparameters can be controlled to continue to cool the subject's skinafter detecting the partial or total freeze event and to maintain apartially or totally frozen state of the portion of the skin for aperiod of time long enough to alter a level of production by theexocrine glands. In one embodiment, the period of time is longer than apredetermined threshold period of time, such as 10 seconds, 20 seconds,or other selected period of time. If the epidermis is overly frozen,hyperpigmentation (skin darkening) or hypopigmentation (skin lightening)can result, which is often undesirable. The cooling device and treatmentparameters can be controlled so as to not cause either or bothhypopigmentation or hyperpigmentation more than a day followingtreatment.

At least some embodiments are systems and methods for selectivenon-invasive cooling of tissue sufficiently deep to affect glands.Axilla apocrine sweat glands or eccrine sweat glands on the palms of thehands can be at different tissue depths than sebaceous glands withinacne-prone regions (e.g., regions along the face, chest, shoulders, orback). The systems and methods disclosed herein can controllably cooltissue at specific depths for injuring targeted glands. In variousembodiments, a zone of maximum cooling or maximum freezing can occur atdepths between about 1 mm to about 5 mm, between about 2 mm and about 5mm, between about 3 mm and about 5 mm, or between about 4 mm and about 5mm. Other depths can be selected based on the location of the targetedstructures. In some embodiments, a treatment site can be cooled to atemperature equal to or lower than about 0° C., −5° C., −10° C., −15°C., −20° C., or −25° C. for a treatment period, and either be in asupercooled state, a partial frozen state, or totally frozen state. Thetreatment period can be equal to or greater than about 1 second, 2seconds, 3 seconds, 5 seconds, 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, or other time periods selected based on the desiredthermal injury. In some supercooling embodiments, the skin is cooled toa supercooled temperature and the epidermis is then warmed to anon-freezing temperature. After warming the epidermis, supercooledtissue is nucleated to initiate the freeze event in the supercooledskin. A freezing point of a material is most reliably ascertained bywarming frozen material slowly and measuring a temperature at whichmelting begins to occur. This temperature is generally not ambiguous ifthe material is slowly warmed. Partial melting will begin to occur atthe freezing/melting point. Conversely, if a non-frozen material iscooled, its freezing/melting point is harder to ascertain since it isknown that many materials can simply “supercool,” that is they can becooled to a bulk temperature below their freezing/melting point andstill remain in a non-frozen state. As used herein, “supercooling,”“supercooled,” “supercool,” etc., refers to a condition in which amaterial is at a temperature below its freezing/melting point but isstill in an unfrozen or mostly unfrozen state.

With or without freezing, at least some embodiments of the technologyare directed to controlling a cooling device or providing other meansfor sufficiently protecting the epidermis from injuries that causehyperpigmentation (skin darkening) or hypopigmentation (skinlightening). The other means for protection can include, withoutlimitation, heating the epidermis to a non-freezing temperature whiledeeper tissue remains cold to induce injury thereto and/or applying acryoprotectant to a surface of the skin to provide freeze protection tothe epidermis while allowing deeper tissue or structures to be moreaffected by the cooling/cold treatment.

Applicators disclosed herein can include one or more elements (e.g.,resistive heaters, electrodes, transducers, vibrators, etc.) fordelivering energy, such as thermal energy, electromagnetic energy,infrared energy, light energy, ultraviolet energy, radiofrequencyenergy, microwave energy, ultrasound energy (e.g., low frequencyultrasound, high frequency ultrasound, etc.), mechanical massage, and/orelectric fields (e.g., AC or DC electric fields). The energy can inhibitor reduce freeze damage or cooling damage in non-targeted regions.Thermal energy can be used to protect non-targeted tissue, such asfacial subcutaneous fat, when cryogenically treating superficial facialdermal structures. Additionally or alternatively, non-targeted regionscan be protected by a chemical cryoprotectant. In addition to targetingglands (e.g., exocrine glands such as sebaceous glands, apocrine sweatglands, eccrine sweat glands, etc.), applicators can be configured totarget other structures, such as collagen and/or elastin for skintightening and dermal thickening, nerve tissue (e.g., superficialnerves), and/or hair follicles.

At least some aspects of the technology are directed to systems andmethods that enable supercooling of target regions. Aspects of thedisclosure are further directed to systems or methods for protectingnon-targeted cells, such as cells in the dermal and/or epidermal skinlayers, by preventing or limiting thermal damage (e.g., cooling orfreeze damage) during dermatological and related aesthetic proceduresthat require sustained exposure to cold temperatures. For example,treatment systems can supercool treatment sites without causingnucleation and freezing. Non-targeted tissue can be heated to localizethe supercooling, and after localizing the supercooled tissue,supercooled body fluids/lipids can be nucleated by various methods toinitiate a partial or total freeze and to damage, reduce, disrupt,modify or otherwise affect targeted cells.

In some supercooling embodiments, regions with glands can be supercooledeither with or without using any cryoprotectant. Non-targeted region(s)can be heated above their freezing points before initiatingcrystallization of the supercooled tissue. In certain embodiments foraffecting glands in the dermal layer, the skin can be supercooled eitherwith or without affecting the subcutaneous layer. After heating theepidermal layer so that mostly dermal tissue is supercooled, nucleationin the dermal layer can be initiated. Freezing of the supercooled regioncan be promoted without damaging non-targeted tissue or non-targetedanatomical features. Nucleation can be induced by delivering analternating current to the tissue, applying a nucleating solution ontothe surface of the skin (for example one that includes bacteria whichinitiate nucleation), applying fields (e.g., electric fields), and/or bycreating a mechanical perturbation to the tissue, such as by use ofvibration, ultrasound energy, etc.

B. Treatment Sites

FIG. 1 is a schematic cross-sectional view of tissue of a subject inaccordance with one embodiment. The subject's skin 10 includes thedermis 12 located between the epidermis 14 and the subcutaneous layer16. The dermis 12 includes sebaceous glands 17 that produce sebum formoisturizing the skin and hair. Acne is a skin condition typicallycharacterized by excess sebum that may plug hair follicles and/or pores.The level of sebum production may vary between individuals and may varyby body location depending on the number and sizes of the sebaceousglands. Sebum can flow along the healthy hair follicle 20 to moisturizethe hair 23 and/or epidermis 14. When the sebaceous glands 17 produceexcess sebum, it can collect and/or become trapped in hair follicles.Overproduction and/or entrapment of sebum, the waxy substance producedand secreted by sebaceous glands 17, can lead to formation of comedones(e.g., blackheads, whiteheads, etc.) as well as other inflammatoryconditions of the skin associated with acne (e.g., inflamed papules,pustules, nodules, etc.). In some individuals, inflamed follicles andpores can become infected and the condition can potentially lead toscarring of the skin. The illustrated hair follicle 22 is clogged withexcess sebum to form a pimple or red spot. Other medical conditionsassociated with overactive sebaceous glands which produce an excess ofsebum include sebaceous cysts, hyperplasia and sebaceous adenoma.Non-medical, but cosmetically unappealing, conditions associated withoveractive sebaceous glands include oily skin and/or oily hair (e.g., onthe scalp).

Hyperhidrosis is a skin condition characterized by abnormal sweating dueto high secretion levels of sweat glands 26. Eccrine sweat glands arecontrolled by the sympathetic nervous system and regulate bodytemperature. When an individual's body temperature rises, eccrine sweatglands secrete sweat (i.e., water and other solutes) that flows througha gland tubule 28. The sweat can evaporate from the skin surface to coolthe body. Apocrine sweat glands (not shown) secrete an oil-containingsweat into hair follicles 20. The axilla (e.g., armpit) and genitalregions often have a higher concentration of apocrine sweat glands.Hyperhidrosis occurs when sweat glands produce and secrete sweat atlevels above that required for regulation of body temperature, and thecondition can be generalized or localized (i.e., focal hyperhidrosis) tospecific body parts (e.g., palms of hands, soles of feet, brow, scalp,face, underarms, etc.).

FIG. 2 is a schematic cross-sectional view of the skin 10 in FIG. 1showing a reduction of acne after treatment in accordance with aspectsof the present technology. A treatment device in the form of athermoelectric applicator 104 (“applicator 104”) has been applied to andcooled the skin 10 to produce a freeze-induced injury that affected thesebaceous glands 17. Although the reduction in acne is shown while theapplicator 104 is applied to the skin 10, it may take a relatively longperiod of time (e.g., days, weeks, months, etc.) for acne to be reducedafter treatment. The sebum production level of the two sebaceous glands17 along the hair follicle 22 has been substantially reduced to inhibitclogging to minimize, reduce, or eliminate acne. The sweat gland 26 canalso be targeted. For example, the applicator 104 can produce a partialor total freeze event or non-freezing cooling event or supercoolingevent to injure the sweat gland 26 and/or duct 28 in a region of theskin located along the hands, armpits, or other locations with excesssweating. Cryotherapy can be performed any number of times at the samesite or different sites to treat acne, hyperhidrosis, or otherconditions.

C. Cryotherapy

FIG. 3 and the following discussion provide a general description of anexample of a suitable non-invasive treatment system 100 in which aspectsof the technology can be implemented. The treatment system 100 can be atemperature-controlled cooling apparatus for cooling tissue at atargeted treatment site to perform cryotherapy. Physiologicalcharacteristics affected by cryotherapy can include, without limitation,cellular stability, cell/tissue elasticity, cell size, cell number,and/or gland size or secretion ability (e.g., size/diameter of the ductportion). For example, the treatment system 100 can cool the epidermis,dermis, subcutaneous fat, or other targeted tissue to modify glandularfunction, reduce gland size, etc. Non-targeted tissue, such as subdermaltissue or tissue adjacent the targeted exocrine glands, can remaingenerally unaffected. In various embodiments, the treatment system 100can be configured to cool the skin of the patient to selectively affect(e.g., injure, damage, kill) secreting exocrine glandular cells. In aparticular example, cooling can produce a cold shock response to modifya secretion volume from a targeted exocrine gland of the epidermisand/or dermis by affecting protein proliferation and other cellularfunctions. Those skilled in the relevant art will appreciate that otherexamples of the disclosure can be practiced with other treatment systemsand treatment protocols, including invasive, minimally invasive, othernon-invasive medical treatments.

In one example, lipid-producing cells residing in or at least proximateto sebaceous glands (e.g., glandular epithelial cells) present in thedermis of a target region can be targeted by the treatment system 100for the treatment of acne or other skin condition. The lipid-producingcells residing in or proximate to sebaceous glands contribute toproduction of sebum, the waxy and oily secretion that can contribute toacne. For example, the treatment system 100 can be configured to reducea temperature of a dermal layer of skin to reduce the temperature oflipid-producing cells residing in or at least proximate to sebaceousglands such that the targeted lipid-producing cells excrete a loweramount of sebum, such that there are fewer lipid-producing cellsresulting in less sebum production within the targeted sebaceous glands,or in another embodiment, such that the sebaceous glands are destroyed.The treatment system 100 can be configured, for example, to reduce asubject's acne by cooling acne-prone regions of the body.

In another example, secreting glandular cells residing in axillaapocrine sweat glands can be targeted by the treatment system 100 forthe treatment of hyperhidrosis. Apocrine sweat glands comprise a coiledsecretory portion located at the junction of the dermis and thesubcutaneous fat, and a duct portion that funnels the secreted sweatsubstance into a portion of a hair follicle. Secreting glandular cellsresiding in the coiled secretory portion between the dermis and thesubcutaneous layers produce an oily compound and create a secretionsubstance that also includes water and other solutes, such as minerals,lactate and urea to form apocrine sweat. The treatment system 100 can beconfigured to reduce a temperature of a dermal layer of skin (e.g., ator near the axilla) to reduce the temperature of secreting glandularcells residing in the coiled portion of the apocrine sweat glands suchthat the targeted cells excrete a lower amount of oil-containing sweat,such that there are fewer sweat-producing cells resulting in lesssweat/oil production within the targeted apocrine sweat glands, or inanother embodiment, such that the apocrine sweat glands are destroyed.In yet another embodiment, secreting glandular cells residing in orproximate to eccrine sweat glands (e.g., in the palms of the hands,soles of the feet, scalp, face, axilla region, etc.) can be targeted bythe treatment system 100 for the treatment of focal hyperhidrosis atthose treatment sites.

Referring to FIG. 3, the applicator 104 is suitable for altering afunction of a gland residing in skin without affecting subcutaneoustissue (e.g., subcutaneous adipose tissue, etc.). The applicator 104 canbe suitable for modifying a secretion volume, level, biochemicalcontent, or other factor from targeted exocrine glands (e.g., sebaceousglands 17 or sweat glands 26 shown in FIG. 1) by cooling the skinwithout permanently altering cells of non-targeted tissue (e.g., deepdermal tissue, subdermal tissue, etc.). Without being bound by theory,the effect of cooling selected cells (e.g., glandular secreting cells,hair follicles, etc.) is believed to result in, for example, proteinalteration (e.g., synthesis of heat shock proteins, stress proteins,etc.), cell size alteration, cell division, wound remodeling (e.g.,thickening of the epidermis, contraction of the epidermis, etc.),fibrosis, and so forth. By cooling the skin to a sufficient lowtemperature, target cells that contribute to the presence of undesiredfeatures can be selectively affected while non-targeted tissue can beunaffected.

The applicator 104 can be used to perform a wide range of differentcryotherapy procedures. One cryotherapy procedure involves at leastpartially freezing tissue (e.g., cellular structures, intracellularfluid, extracellular fluid, connective tissue etc.) in a target tissueregion to form crystals that alter targeted cells to modify a glandularsecretion characteristic (e.g., volume, content, etc.) withoutdestroying a significant amount of cells in the skin. To avoiddestroying skin cells in a partial freeze embodiment and in anembodiment where tissue is not partially frozen, the surface of thepatient's skin can be cooled to temperatures no lower than, for example,−40° C. for a duration short enough to avoid, for example, excessive iceformation, permanent thermal damage, or lightening or darkening skin,such as significant hypopigmentation (including long-lasting orpermanent hypopigmentation) or hyperpigmentation (including long-lastingor permanent hyperpigmentation) in a period of time following atreatment, such as several hours; one, two, three days; or one, two,three weeks; and longer periods of time following a treatment. Inanother embodiment, undue destruction of skin cells, epidermal cells inparticular, can be avoided by applying heat to the surface of thepatient's skin to heat these skin cells above their freezingtemperature. The patient's skin can be warmed to at least about −30° C.,−25° C., −20° C., −15° C., −10° C., 0° C., 10° C., 20° C., 30° C., orother temperature sufficient to avoid, for example, excessive iceformation, permanent thermal damage, or significant hypopigmentation orhyperpigmentation of the non-targeted and/or epidermal tissue. In sometreatments, skin can be cooled to produce partial or total freeze eventsthat cause apoptotic damage to skin tissue without causing significantdamage to adjacent subcutaneous tissue. Apoptosis, also referred to as“programmed cell death”, of the skin tissue can be a genetically-induceddeath mechanism by which cells slowly self-destruct without incurringdamage to surrounding tissues. Other cryotherapy procedures may causenon-apoptotic responses.

In some tissue-freezing procedures, the applicator 104 can controllablyfreeze tissue (e.g., organic matter, inorganic matter, etc.) within atissue region and can detect the freeze event. After detecting thefreeze event, the applicator 104 can periodically or continuously removeheat from the target tissue to keep a volume of target tissue frozen fora suitable predetermined length of time to elicit a desired response andyet a short enough period of time to not cause any unwanted or undesiredside effects, such as hypopigmentation and/or hyperpigmentation. Thedetected freeze event can be a partial freeze event, a complete freezeevent, etc. In some embodiments, the controlled freezing causestightening of the skin, thickening of the skin, and/or a cold shockresponse at the cellular level in the skin. In one tissue-freezingtreatment, the applicator 104 can produce a partial or total freezeevent that includes, without limitation, partial or full thicknessfreezing of the patient's skin for a relatively short limit to avoidcooling the adjacent subcutaneous tissue to a low enough temperature forsubcutaneous cell death. The freezing process can include forming icecrystals in intracellular and/or extracellular fluids, and the icecrystals can be small enough to avoid disrupting membranes so as toprevent significant permanent tissue damage, such as necrosis. Somepartial freeze events can include freezing mostly extracellular materialwithout freezing a substantial amount of intercellular material. Inother procedures, partial freeze events can include freezing mostlyintercellular material without freezing a substantial amount ofextracellular material. The frozen target tissue can remain in thefrozen state long enough to affect the target tissue but short enough toavoid damaging non-targeted tissue or damaging an undue amount of thetarget tissue. For example, the duration of the freeze event can beshorter than about 20 seconds, 30 seconds, or 45 seconds or about 1, 2,3, 4, 5 or 10 minutes. The frozen tissue can be thawed to preventnecrosis and, in some embodiments, can be thawed within about 20seconds, 30 seconds, or 45 seconds or about 1, 2, 3, 4, 5, or 10 minutesafter initiation of the freeze event.

The mechanisms of cold-induced tissue injury in cryotherapy can alsoinvolve direct cellular injury (e.g., damage to the cellular machinery)and/or vascular injury in embodiments where freezing occurs and inembodiments where freezing does not occur. For example, cell injury canbe controlled by adjusting thermal parameters, including (1) coolingrate, (2) end (or minimum) temperature, (3) time held at the minimumtemperature (or hold time), (4) temperature profile, and (5) thawingrate. In one example, increasing the hold time can allow theintracellular compartments to equilibrate with the extracellular space,thereby increasing cellular dehydration. Another mechanism ofcold-induced injury is cold and/or freeze-stimulated immunologic injury.Without being bound by theory, it is believed that after cryotherapy,the immune system of the host is sensitized to the disrupted tissue(e.g., lethally damaged tissue, undamaged tissue, or sublethally injuredtissue), which can be subsequently destroyed by the immune system.

One mechanism to selectively affect oil and/or sebum-producing andsecreting glandular cells is to cool the targeted tissue to temperaturesthat affect lipid-rich cells (which generally freeze or are damaged attemperatures which are higher than temperatures at which non-lipid richcells are damaged) but that do not negatively affect non-lipid richcells, such as other cells in the epidermal and dermal layers at orproximate to the treatment site which have lower temperature damagethresholds. The treatment system 100 can be configured to cool thesubject's skin for a period of time long enough so that lipid-rich cells(sebum or oil-producing cells residing in or at least proximate toexocrine glands) in the dermal layer are substantially affected tocause, for example, apoptosis. Apoptosis of lipid-rich cells may be adesirable outcome for beneficially altering (e.g., reducing) glandularfunction that may contribute to an undesirable appearance (e.g., acne,hyperhidrosis, etc.). Apoptosis of glandular lipid-rich cells caninvolve ordered series of biochemical events that induce cells tomorphologically change. These changes include cellular blebbing, loss ofcell membrane asymmetry and attachment, cell shrinkage, chromatincondensation, and chromosomal DNA fragmentation. Injury via an externalstimulus, such as cold exposure, is one mechanism that can induceapoptosis in cells. Nagle, W. A., Soloff, B. L., Moss, A. J. Jr., Henle,K. J. “Cultured Chinese Hamster Cells Undergo Apoptosis After Exposureto Cold but Nonfreezing Temperatures” Cryobiology 27, 439-451 (1990).One aspect of apoptosis, in contrast to cellular necrosis (a traumaticform of cell death causing, and sometimes induced by, localinflammation), is that apoptotic cells express and display phagocyticmarkers on the surface of the cell membrane, thus marking the cells forphagocytosis by, for example, macrophages. As a result, phagocytes canengulf and remove the dying cells (e.g., the lipid-rich cells) withouteliciting an immune response.

Without being bound by theory, one mechanism of apoptotic lipid-richcell death by cooling is believed to involve localized crystallizationof lipids within the adipocytes at temperatures that may or may notinduce crystallization in non-lipid-rich cells. The crystallized lipidsmay selectively injure these cells, inducing apoptosis (and may alsoinduce necrotic death if the crystallized lipids damage or rupture thebilayer lipid membrane of the glandular cell). Another mechanism ofinjury involves the lipid phase transition of those lipids within thecell's bilayer lipid membrane, which results in membrane disruption,thereby inducing apoptosis. This mechanism is well documented for manycell types and may be active when lipid-rich cells, are cooled. Mazur,P., “Cryobiology: the Freezing of Biological Systems” Science, 68:939-949 (1970); Quinn, P. J., “A Lipid Phase Separation Model of LowTemperature Damage to Biological Membranes” Cryobiology, 22: 128-147(1985); Rubinsky, B., “Principles of Low Temperature Preservation” HeartFailure Reviews, 8, 277-284 (2003). Other possible mechanisms oflipid-rich cell damage, described in U.S. Pat. No. 8,192,474, relates toischemia/reperfusion injury that may occur under certain conditions whensuch cells are cooled as described herein. For instance, duringtreatment by cooling as described herein, targeted glandular tissue mayexperience a restriction in blood supply and thus be starved of oxygendue to isolation while pulled into, e.g., a vacuum cup, or simply as aresult of the cooling which may affect vasoconstriction in the cooledtissue. In addition to the ischemic damage caused by oxygen starvationand the build-up of metabolic waste products in the tissue during theperiod of restricted blood flow, restoration of blood flow after coolingtreatment may additionally produce reperfusion injury to the glandularcells due to inflammation and oxidative damage that is known to occurwhen oxygenated blood is restored to tissue that has undergone a periodof ischemia. This type of injury may be accelerated by exposing theglandular cells to an energy source (via, e.g., thermal, electrical,chemical, mechanical, acoustic or other means) or otherwise increasingthe blood flow rate in connection with or after cooling treatment asdescribed herein. Increasing vasoconstriction in such glandular tissueby, e.g., various mechanical means (e.g., application of pressure ormassage), chemical means or certain cooling conditions, as well as thelocal introduction of oxygen radical-forming compounds to stimulateinflammation and/or leukocyte activity in glandular tissue may alsocontribute to accelerating injury to such cells. Other yet-to-beunderstood mechanisms of injury may also exist.

In addition to the apoptotic mechanisms involved in lipid-rich celldeath, local cold exposure may induce lipolysis (i.e., fat metabolism)of lipid-rich cells. For example, cold stress has been shown to enhancerates of lipolysis from that observed under normal conditions whichserves to further increase the volumetric reduction of lipid-rich cells.Vallerand, A. L., Zamecnik. J., Jones, P. J. H., Jacobs, I. “Cold StressIncreases Lipolysis, FFA Ra and TG/FFA Cycling in Humans” Aviation,Space and Environmental Medicine 70, 42-50 (1999).

Without being bound by theory, the effect of cooling on lipid-rich cellsis believed to result in, for example, membrane disruption, shrinkage,disabling, destroying, removing, killing, or another method oflipid-rich cell alteration. For example, when cooling glandular tissuein the dermal layer to a temperature lower than 37° C., lipid-rich cells(e.g., sebum-producing cells within sebaceous glands, oil-producingcells within sweat glands) can selectively be affected. In general, theremaining cells in the epidermis and dermis of the subject 101 havelower amounts of lipids compared to the secreting lipid-rich cellsforming portions of the glandular tissue. Since lipid-rich cells aremore sensitive to cold-induced damage than non-lipid-rich cells, it ispossible to use non-invasive or minimally invasive cooling to destroylipid-rich cells without destroying the overlying or surrounding skincells. In some embodiments, lipid-rich cells within secretory glands aredestroyed while the appearance of overlying skin is improved.

Lipid-containing cells are more easily damaged by low temperatures thanthe non-lipid rich dermal and epidermal cells, and as such, thetreatment system 100 can be used to cool the desired layers of skin atthe treatment sites to a temperature above the freezing point of water,but below the freezing point of fat. It is believed that thetemperatures can be controlled to manage damage in the non-lipid-richcells of the epidermis and/or dermis via, for example, intracellularand/or extracellular ice formation. Excessive ice formation may rupturethe cell wall and may also form sharp crystals that locally pierce thecell wall as well as vital internal organelles. Ice crystal initiationand growth can be managed to avoid cell death in the non-targetedportions of the skin. When extracellular water freezes to form ice, theremaining extracellular fluid becomes progressively more concentratedwith solutes. The high solute concentration of the extracellular fluidmay cause intracellular fluid to be driven through the semi-permeablecellular wall by osmosis resulting in cell dehydration. The applicator104 can reduce the temperature of the lipid-rich cells found in thetargeted glandular tissue such that the lipid rich cells are destroyedwhile the temperature of the remaining skin cells are maintained at ahigh enough temperature to produce non-destructive freeze events in theskin. Cryoprotectants and/or thermal cycling can prevent destructivefreeze events in the non-targeted skin tissue.

At least some aspects of the technology are directed to systems andmethods of treating a patient by cooling a surface of the patient's skinto a temperature sufficiently low to cause supercooling of targetedtissue below the skin surface. The surface of the skin can then beheated to a non-supercooled temperature while the targeted tissueremains in a supercooled state. After heating the non-targeted tissue,the supercooled targeted tissue can be controllably frozen. In someembodiments, nucleation can be controlled to cause partial or totalfreezing. The applicator 104 can be kept generally stationary relativeto the treatment site during cooling to avoid pressure changes thatwould cause nucleation. After heating non-targeted tissue, theapplicator can cause nucleation in the supercooled targeted tissue by,for example, varying applied pressures, delivering energy (e.g.,ultrasound energy, RF energy, ultrasound energy), applying fields (e.g.,electric fields), or providing other perturbations (e.g., vibrations,pulses, etc.), as well as combinations thereof. Because the non-targetedtissue has been warmed to a non-supercooled state, it does notexperience a freeze event. In some embodiments, the applicator caninclude one or more movable plates (e.g., plates movable to vary appliedpressures), rotatable eccentric masses, ultrasound transducers,electrical current generators, or other elements capable of providingnucleating perturbations. Vacuum applicators can increase and decreasevacuum levels to massage tissue, vary applied pressures, etc.

Once catalyzed, the partial or total freeze event can be detected, and acooling device associated with the treatment system 100 can becontrolled to continue cooling the patient's skin so as to maintain afrozen state of targeted tissue for a desired period of time. The skincan be periodically or continuously cooled to keep a sufficient volumeof the tissue in a frozen state. In some embodiments, the targetedtissue can be kept frozen for longer or shorter than about, for example,1 second, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 1 minute,several minutes, or other time period selected to reduce or limitfrostbite or necrosis. Further, the temperature of the upper tissue ofthe skin can be detected, and the treatment system can be controlled toapply heat to the surface of the patient's skin for a preselected periodof time to prevent freezing of non-targeted tissue. The preselectedperiod of time can be longer or shorter than about 1, 2, 3, 4, or 5seconds. Accordingly, non-targeted tissue can be protected without usinga chemical cryoprotectant that may cause unwanted side effects.Alternatively, a cryoprotectant can also be used if an additional marginof safety for some tissue, such as the epidermis, is desired.

D. Treatment Systems and Methods of Treatment

FIG. 3 is a partially schematic, isometric view of a treatment systemfor non-invasively treating targeted structures in a human subjects bodyin accordance with an embodiment of the technology. The treatment system100 can include the applicator 104, a connector 103, and a base unit106. After applying the applicator 104 to a subject 101, it can coolcells in or associated with targeted glands. For example, the applicator104 can be applied to acne-prone regions and can transcutaneously coolskin to reduce the temperature of lipid-producing cells residing in orat least proximate to sebaceous glands (e.g., glandular epithelialcells) to lower the amount of secreted sebum and thereby eliminate,reduce, or limit acne. The applicator 104 can also cool sweat glands andassociated structures to treat hyperhidrosis.

The connector 103 can be an umbilical cord that provides energy, fluid,and/or suction from the base unit 106 to the applicator 104. The baseunit 106 can include a fluid chamber or reservoir 105 (illustrated inphantom line) and a controller 114 carried by a housing 125 with wheels126. The base unit 106 can include a refrigeration unit, a coolingtower, a thermoelectric chiller, heaters, or any other devices capableof controlling the temperature of coolant in the fluid chamber 105 andcan be connectable to an external power source and/or include aninternal power supply 110 (shown in phantom line). The power supply 110can provide electrical energy (e.g., a direct current voltage) forpowering electrical elements of the applicator 104. A municipal watersupply (e.g., tap water) can be used in place of or in conjunction withthe fluid chamber 105. In some embodiments, the system 100 includes apressurization device 117 that can provide suction and can include oneor more pumps, valves, and/or regulators. Air pressure can be controlledby a regulator located between the pressurization device 117 and theapplicator 104. If the vacuum level is too low, tissue may not beadequately (or at all) held against the applicator 104, and theapplicator 104 may tend to move along the patient's skin. If the vacuumlevel is too high, undesirable patient discomfort and/or tissue damagecould occur. A vacuum level can be selected based on the characteristicsof the tissue and desired level of comfort.

An operator can control operation of the treatment system 100 using aninput/output device 118 of the controller 114. The input/output device118 can display the state of operation of the applicator 104 andtreatment information. In some embodiments, the controller 114 canexchange data with the applicator 104 via a wired connection or awireless or an optical communication link and can monitor and adjusttreatment based on, without limitation, one or more treatment profilesand/or patient-specific treatment plans, such as those described, forexample, in commonly assigned U.S. Pat. No. 8,275,442. In someembodiments, the controller 114 can be incorporated into the applicator104 or another component of the system 100.

Upon receiving input to start a treatment protocol, the controller 114can cycle through each segment of a prescribed treatment plan. Segmentsmay be designed to freeze tissue, thaw tissue, supercool tissue,nucleate supercooled tissue, and so on. In so doing, the power supply110 and the fluid chamber 105 can provide power and coolant to one ormore functional components of the applicator 104, such as thermoelectriccoolers (e.g., TEC “zones”), to begin a cooling cycle and, in someembodiments, activate features or modes such as vibration, massage,vacuum, etc. The controller 114 can receive temperature readings fromtemperature sensors, which can be part of the applicator 104 orproximate to the applicator 104, the patient's skin, a patientprotection device, etc. It will be appreciated that while a targetregion of the body has been cooled or heated to the target temperature,in actuality that region of the body may be close but not equal to thetarget temperature, e.g., because of the body's natural heating andcooling variations. Thus, although the system 100 may attempt to heat orcool tissue to the target temperature or to provide a target heat flux,a sensor may measure a sufficiently close temperature or heat flux. Ifthe target temperature or the flux has not been reached, power can beincreased or decreased to change heat flux to maintain the targettemperature or “set-point” selectively to affect targeted tissue.

FIG. 4 is a cross-sectional view of the connector 103 taken along line4-4 of FIG. 3 in accordance with at least some embodiments of thetechnology. The connector 103 can be a multi-line or multi-lumen conduitwith a main body 179 (e.g., a solid or hollow main body), a supply fluidline or lumen 180 a (“supply fluid line 180 a”), and a return fluid lineor lumen 180 b (“return fluid line 180 b”). The main body 179 may beconfigured (via one or more adjustable joints) to “set” in place for thetreatment of the subject. The supply and return fluid lines 180 a, 180 bcan be tubes made of polyethylene, polyvinyl chloride, polyurethane,and/or other materials that can accommodate circulating coolant, such aswater, glycol, synthetic heat transfer fluid, oil, a refrigerant, and/orany other suitable heat conducting fluid. In one embodiment, each fluidline 180 a, 180 b can be a flexible hose surrounded by the main body179. Referring to FIGS. 3 and 4, coolant can be continuously orintermittently delivered to the applicator 104 via the supply fluid line180 a and can circulate through the applicator 104 to absorb heat. Thecoolant, which has absorbed heat, can flow from the applicator 104 backto the base unit 106 via the return fluid line 180 b. For warmingperiods, the base unit 106 (FIG. 3) can heat the coolant such that warmcoolant is circulated through the applicator 104. Referring now to FIG.4, the connector 103 can also include one or more electrical lines 112for providing power to the applicator 104 (FIG. 3) and one or morecontrol lines 116 for providing communication between the base unit 106(FIG. 3) and the applicator 104 (FIG. 3). To provide suction, theconnector 103 can include one or more vacuum tubes or lines 119.

FIG. 5 is a schematic cross-sectional view of a treatment device in theform a non-invasive applicator 204 suitable for the treatment system 100in accordance with an embodiment of the present technology. Theapplicator 204 can cool tissue to produce a thermal event (e.g.,supercooling event, freezing event, cooling event, etc.) in a targetedcooling or event zone 232 (shown in phantom line). The controller 114can be programmed to cause the applicator 204 to cool the subject's skinafter detecting the thermal event (e.g., freeze event, supercoolingevent, reaching a target temperature with or without causing a freezeevent, or other detectable thermal event) so that the thermal eventlasts a sufficient period of time to substantially alter secretionproduction levels of the glands. In some procedures, a cooling event canlast long enough to permanently decrease production levels of the glandsin the event zone 232 in which most significant damage occurs. Forexample, most or substantially all the sebaceous glands 17 in the eventzone 232 can be destroyed, reduced, or otherwise altered to reduce orotherwise modify sebum production.

A central region 234 of the event zone 232 can be deeper than most ofthe epidermal layer 14 to avoid or limit damage to epidermal tissuewhich could lead to undesired skin coloration changes. A distance 237between the surface of the skin and the event zone 232 can be generallyequal to or greater than the thickness of the epidermis 14 and, in someembodiments, can be between about 0.1 mm to about 1.5 mm, between about0.5 mm to about 1.5 mm, or other distances selected to keep thermaldamage to epidermal tissue at or below an acceptable level. The eventzone 232 can be at a maximum depth 239 between about 0.25 mm to about 5mm, between about 0.25 mm to about 6 mm, between about 0.3 mm to about 5mm, between about 0.3 mm to about 6 mm, between about 0.5 mm to about 5mm, between about 0.5 mm to about 6 mm, or other depths selected toavoid or limit injures to deeper non-targeted tissue (e.g., subcutaneoustissue 16) or structures. The height 241 of the event zone 232 can bebetween about between about 0.1 mm to about 6 mm, between about 0.1 mmto about 3.5 mm, between about 0.3 mm to about 5 mm, between about 1 mmto about 3 mm, or other heights selected based on the thickness of thedermis 12. For example, the height 241 can be slightly greater than thethickness of the dermis 12 to keep thermal-injuries, if any, to theepidermis 14 and/or subcutaneous layer 16 at an acceptable level. Insome embodiments, the event zone 232 can be generally centered in thedermis 12, and the height 241 can be less than the thickness of thedermis 12. Adjacent epidermal and subdermal tissue may also be cooledbut can be at a sufficiently high temperature to avoid or limit thermalinjury. The location and dimensions (e.g., height 241, width, length,etc.) of the event zone 232 can be selected based on the location of thetargeted structures, tissue characteristics at the target site, etc. Insome embodiments, the event zone 232 can comprise significant amounts ofepidermal and dermal tissue. For example, the event zone 232 cancomprise most of the tissue located directly between the cooledheat-exchanging surface 219 and the subcutaneous tissue 16. In someprocedures, at least about 60%, 70%, 80%, 90%, or 95% of the tissuedirectly between the heat-exchanging surface 219 and the subcutaneouslayer 16 can be located within the event zone 232. Heating,cryoprotectants, and/or supercooling techniques can be used to avoidinjury to the epidermal tissue.

The applicator 204 can include a cooling device 210 and an interfacelayer 220. The cooling device 210 can include, without limitation, oneor more thermoelectric coolers 213, each including one or more thethermoelectric elements (e.g., Peltier-type TEC elements) powered byelectrical energy from a treatment tower or base unit (e.g., base unit106 of FIG. 3) or another power source. The thermoelectric coolers 213can also include controllers, temperature regulators, sensors, and otherelectrical components. For example, each thermoelectric cooler 213 caninclude an array of individually controlled thermoelectric elements anda controller. In some embodiments, the controller 114 can be programmedto control operation of the thermoelectric coolers 213 to remove heatfrom tissue at a sufficient rate to produce a cooling event (e.g., afreeze or non-freeze event) that can cause destruction of targetedcells. In freeze event embodiments, ice crystals may nucleate and growin the event zone 232 and can damage cells to inhibit or otherwiseaffect gland function, but they may also locally pierce a sufficientamount of the cell walls to destroy the glands.

The applicator 204 can include sensors configured to measure tissueimpedance, pressure applied to the subject, optical characteristics oftissue, and/or tissue temperatures. As described herein, sensors can beused to monitor tissue and, in some embodiments, to detect events. Thenumber and types of sensors can be selected based on the treatment to beperformed. In some embodiments, the applicator 204 can include acommunication component 215 that communicates with the controller 114 toprovide a first sensor reading 242, and a sensor 217 that measures,e.g., temperature of the cooling device 210, heat flux across a surfaceof or plane within the cooling device 210, tissue impedance, applicationforce, tissue characteristics (e.g., optical characteristics), etc. Theinterface layer 220 can be a plate, a film, a covering, a sleeve, asubstance reservoir or other suitable element described herein and, insome embodiments, may serve as the patient protection device describedherein.

The interface layer 220 can also contain a similar communicationcomponent 225 that communicates with the controller 114 to provide asecond sensor reading 244 and a sensor 227 that measures, e.g., the skintemperature, temperature of the interface layer 220, heat flux across asurface of or plane within the interface layer 220, contact pressurewith the skin of the patient, etc. For example, one or both of thecommunication components 215, 225 can receive and transmit information,such as temperature and/or heat flux information as determined by one orboth of sensors 217, 227. The sensors 217, 227 are configured to measurea parameter of the interface without substantially impeding heattransfer between the applicator 204 and the patient's skin.

In certain embodiments, the applicator 204 can include a sleeve or liner250 (shown schematically in phantom line) for contacting the patient'sskin 230, for example, to prevent direct contact between the applicator204 and the patient's skin 230, and thereby reduce the likelihood ofcross-contamination between patients, minimize cleaning requirements forthe applicator 204, etc. The sleeve 250 can include a first sleeveportion 252 and a second sleeve portion 254 extending from the firstsleeve portion. The first sleeve portion 252 can contact and/orfacilitate contact of the applicator 204 with the patient's skin 230,while the second sleeve portion 254 can be an isolation layer extendingfrom the first sleeve portion 252. The second sleeve portion 254 can beconstructed from latex, rubber, nylon, Kevlar®, or other substantiallyimpermeable or semi-permeable material. The second sleeve portion 254can prevent contact between the patient's skin 230 and the applicator204, among other things. Further details regarding a patient protectiondevice may be found in U.S. Patent Publication No. 2008/0077201.

The applicator 204 can be manually held against the subject's skin andcan also include a belt or other retention devices (not shown) forholding the applicator 204 against the skin. The belt may be rotatablyconnected to the applicator 204 by a plurality of coupling elements thatcan be, for example, pins, ball joints, bearings, or other types ofrotatable joints. Alternatively, retention devices can be rigidlyaffixed to the end portions of the interface layer 220. Further detailsregarding suitable belt devices or retention devices may be found inU.S. Patent Publication No. 2008/0077211. In conjunction with or inplace of a retention device, a vacuum can assist in forming a contactbetween the applicator 204 (such as via the interface layer 220 orsleeve 250) and the patient's skin 230.

The sensors 217, 227 can serve as event detect sensors that provideoutput (e.g., sensor readings 242, 244) collected in real-time becausereal-time processing of such output can help correctly and efficaciouslyadminister treatment. The output can be detected temperatures, heatfluxes, optical characteristics of tissue, mechanical characteristics oftissue, etc. In one example, real-time data processing is used to detectcooling events and to determine a period of time to continue cooling thepatient's skin after one or more cooling events are detected. Tissue canbe monitored to keep a desired region or volume of tissue in the cooledstate (e.g., at least partially or totally frozen state) for a period oftime selected by the controller 114 or an operator. The period of timecan be equal to or longer than about, for example, 5 seconds, 10seconds, 30 seconds, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 30 minutes, 1 hour,or other suitable period of time. In some procedures, the cooling eventis a freeze event that lasts a period of time which is longer than 10seconds and shorter than 10 minutes.

Optionally, the applicator 204 can include one or more features usedwith supercooling. For example, the interface layer 220 can include oneor more nucleation elements 231, 233 in the form of positive andnegative electrodes for heating the skin using alternating currentheating. For radiofrequency induced nucleation, the nucleation elements231, 233 can be radiofrequency electrodes. The power supply 110 (FIG. 3)can include an RF generator for driving the elements 231, 233. Thenucleation elements 231, 233 can also be configured to provide changesin applied pressure to cause nucleation. Any number of different typesof nucleation elements can be incorporated into the interface layer 220or other components of the applicator 204 to provide the ability tocontrollably nucleate supercooled tissue.

Although the thermoelectric elements 213 can heat tissue, the applicator204 can also include dedicated heating elements used to, for example,thaw tissue. FIG. 5 shows the interface layer 220 including heaters 235for generating heat delivered to the surface of the skin 230. Theheaters 235 can be resistive heaters, Peltier devices, or otherthermoelectric elements. Optionally, the nucleation elements 231, 233can also be used to control the temperature of the skin 230. Forexample, the nucleation elements 231, 233 can include RF electrodes thatcooperate to deliver RF energy to heat the skin 230 or deeper tissue.

Multiple applicators may be concurrently or sequentially used during atreatment session, and such applicators can include, without limitation,vacuum applicators, belt applicators, and so forth. Each applicator maybe designed to treat identified portions of the patient's body, such asthe chin, cheeks, forehead, back, shoulders, arms, pectoral areas,armpits, genital region, palms of hands, soles of feet and so forth. Forexample, a vacuum applicator may be applied at the back region, and thebelt applicator may be applied around the thigh region, either with orwithout massage or vibration. Exemplary applicators and theirconfigurations usable or adaptable for use with the treatment system 100are described in, e.g., U.S. Pat. No. 8,834,547 and commonly assignedU.S. Pat. No. 7,854,754 and U.S. Patent Publication Nos. 2008/0077201,2008/0077211, and 2008/0287839, which are incorporated by reference intheir entireties.

FIGS. 6A to 6C illustrate treatment devices suitable for use withtreatment systems disclosed herein in accordance with embodiments of thetechnology. FIG. 6A is a schematic, cross-sectional view illustrating anapplicator 260 for non-invasively removing heat from target areas of asubject 262. The applicator 260 can include a heat-exchanging unit orcooling device 264 (shown in phantom line) and an interface layer 265(shown in phantom line). The interface layer 265 can have a rigid orcompliant concave surface 267. When the applicator 260 is held againstthe subject, the subject's tissue can be pressed against the curvedsurface 267. In some treatments, the compliant concave surface 267 canbe suitable for being applied to a subject's chin, cheek, forehead, orother contoured body area. One or more vacuum ports can be positionedalong the surface 267 to draw the skin 262 against the surface 267. Theconfiguration of the applicator 260 can be selected based on thetreatment site.

FIG. 6B is a schematic, cross-sectional view illustrating an applicator270 that can include a heat-exchanging unit 274 having a rigid orcompliant convex surface 276 configured to be applied to concave regionsof the subject. Advantageously, the convex surface 276 can spread tissueto reduce the distance between the convex surface 276 and targetedtissue under the convex surface 276. In some treatments, the applicator270 can be applied to the axilla (i.e., armpit) region to affectapocrine sweat glands.

FIG. 6C is a schematic, cross-sectional view illustrating an applicator280 including a surface 282 movable between a planar configuration 284and a non-planar configuration 285 (shown in phantom). The surface 282is capable of conforming to the treatment site to provide a largecontact area. In some embodiments, the surface 282 can be sufficientlycompliant to conform to highly contoured regions of a subject's facewhen the applicator 280 is pressed against facial tissue. In otherembodiments, the applicator 280 can include actuators or other devicesconfigured to move the surface 282 to a concave configuration, a convexconfiguration, or the like. The surface 282 can be reconfigured to treatdifferent treatment sites of the same subject or multiple subjects.

FIG. 6D is a side view of an applicator 289 configured to treat atargeted feature. Targeted features can be, without limitation, cysts,glands, or other discrete features. The applicator 289 can include amain housing 290, a cooling assembly 291, and a control element 292. Themain housing 290 can be a tubular member that surrounds and protects thecooling assembly 291. The cooling assembly 291 can include, withoutlimitation, a cooling device or element 293 (“cooling element 293”) anda connector 294. The cooling element 293 can be connected to anotherdevice (e.g., a control tower or base unit) by the connector 294. Theconnector 294 can be a rod that is moved distally (indicated by arrow295) or proximally (indicated by arrow 296) to move the cooling element293 along a passageway of the housing 290. The connector 294 can includeone or more conduits, wires, passageways, or other features forproviding energy (e.g., electrical energy, radiofrequency energy, etc.),coolant, a vacuum, or the like. In some embodiments, the connector 294can be an umbilical rod that provides energy, fluid, and/or suction. Theapplicator 289 can include sensors or other applicator componentsdisclosed herein. For example, the applicator 289 can include sensorsconfigured to measure tissue impedance, pressure applied to the subject,optical characteristics of tissue, and/or tissue temperatures in orderto monitor tissue and, in some embodiments, to detect events, such aspartial or complete freeze events.

FIG. 6E is a cross-sectional view of a distal portion of the applicator289. The cooling element 293 is spaced apart from an opening 303 forreceiving a feature 297 to be treated. The connector 294 can be pusheddistally (indicated by arrow 299) to move the cooling element 293relative to a longitudinal axis 305 of the applicator 289. In someembodiments, the connector 294 is manually moved through the housing290. In other embodiments, the applicator 289 can include or be usedwith a drive device configured to move the connector 294. The drivedevice can include, without limitation, one or more motors (e.g., drivemotors, stepper motors, etc.), sensors (e.g., position sensors),controllers, or other components.

FIG. 6F is a cross-sectional view of the applicator 289 after thecooling element 293 thermally contacts the target feature 297. In someembodiments, the cooling element 293 can have a generally concavesurface 301 for contacting a large area of the protruding target feature297, such as a sebaceous cyst, sudoriferous cyst, cyst of Zeis,hidrocystoma, bulging gland, acne, or other treatable feature.

The control element 292 can be used to adjust the cooling element 293by, for example, bending or otherwise adjusting the configuration of thecooling element 293. The curvature of the surface 301 can be increasedor decreased by moving the control element 292 inwardly or outwardly,respectively. The control element 292 can include, without limitation,one or more clamps, bands, locking features, etc. for adjusting theconfiguration of the distal end of the main housing 290 and coolingelement 293. The cooling element 293 can be flexible to comfortablyengage the target features, such as a bulging cyst. In rigidembodiments, a physician can select a curved cooling element 293 with aconfiguration (e.g., a partially spherical shape, partially ellipticalshape, etc.) selected based on, for example, the shape and/orconfiguration of targeted feature(s). The cooling element 293 caninclude, without limitation, one or more cooling devices, thermoelectriccoolers, cooling channels, electrodes, heating elements, or otherfeatures for treating the target feature 297. After the cooling element293 contacts the skin 307, the cooling element 293 can actively cool thetarget feature 297.

The applicator 289 can be used to cool/heat relatively small featuresthat may be near sensitive non-targeted tissue. The size of the coolingelement 293 can be selected to minimize treatment of non-targetedtissue. To treat features around the eyes, the applicator 289 can beselected such that most of the tissue received by the cooling element293 is targeted tissue to avoid affecting surrounding tissue. In someprocedures, the applicator 289 can be applied to the subject such thatthe targeted feature is positioned within the opening 303 (FIG. 6E). Thecooling element 293 can be moved through the housing 290 and intothermal contact with the subject's skin 307. In some procedures, thecooling element 293 can be moved back and forth to adjust the appliedpressure, provide a massaging effect, promote nucleation, or the like.The applicator 289 can treat a wide range of features or areas atvarious locations along the subject's body.

FIGS. 7 and 8 are flow diagrams illustrating methods for treating sitesin accordance with embodiments of the technology. Although specificexample methods are described herein, one skilled in the art is capableof identifying other methods that could be performed using embodimentsdisclosed herein. The methods are generally described with reference tothe treatment system 100 of FIG. 3, but the methods may also beperformed by other treatment systems with additional or differenthardware and/or software components.

FIG. 7 is a flow diagram illustrating a method 350 for treating exocrineglands in accordance with embodiments of the technology. Generally, asubject's skin can be cooled to thermally affect a target regioncontaining exocrine glands. Treatment can be monitored in order to keeptissue cooled for a sufficient length of time to affect the exocrineglands. Details of method 350 are discussed below.

At block 352, a treatment device is applied to a subject by placing itsheat-exchanging surface or other feature in thermal contact with thesubject's skin. The surface of the subject's skin can be continuously orperiodically cooled to produce at least one cooling event (e.g., apartial freeze event, a complete freeze event, supercooling event, etc.)in a portion of the skin with exocrine glands. In treatments for acne,the targeted glands can be sebaceous glands and/or supportingstructures, which may be in the epidermis and/or dermis. In treatmentsfor excessive sweating, the targeted glands can be sweat glands and/orsupporting structures.

Rapid cooling can create a thermal gradient with the coldesttemperatures in the region of skin near the treatment device whereasrapid heating can create a thermal gradient with the highesttemperatures in the region of skin near the treatment device. Duringcooling, skin can be frozen for a short enough duration to not establisha temperature equilibrium across the skin and adjacent subcutaneoustissue. Cryoprotectant(s) and/or warming cycle(s) can be used to inhibitfreezing of the uppermost non-targeted layer or layers of skin (e.g.,layers of the epidermis). In some procedures, a cryoprotectant can beapplied to the treatment site to inhibit damage to the epidermis whilecooling and freezing the dermal layer without causing freeze damage tosubcutaneous tissue. As such, the combination of cryoprotectant andcontrolled cooling can produce a desired cooling zone, and cooling ofthe cooling zone can be controlled to either have a non-freeze coolingevent, a partial freeze event or a total brief freeze event. In someembodiments, the treatment device can non-invasively produce a freezeevent that begins within a predetermined period of time after theapplicator begins cooling the patient's skin. The predetermined periodof time can be equal to or shorter than about 10 seconds, 30 seconds, 60seconds, 90 seconds, 120 seconds, or 150 seconds or longer periods and,in some embodiments, can be from between about 10 seconds to about 150seconds, between about 30 seconds to about 150 seconds, or between about60 seconds to about 150 seconds. In some embodiments, the predeterminedperiod of time can be shorter than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 minutes. A controller (e.g., controller 114 of FIG. 2) can select thepredetermined period of time for producing a cooling event based on thetreatment temperatures, treatment sites, and/or cryotherapy to beperformed. Alternatively, an operator can select the period of time forcooling and can enter it into the controller 114.

In some embodiments, the subject's skin can be cooled to produce apartial freeze event that includes at least some crystallization (e.g.,formation of microscopic ice crystals) in intercellular material (e.g.,fluid, cell components, etc.) and/or extracellular fluid. By avoidingextensive ice crystal formation that would cause frostbite or necrosis,partial freeze events can occur without excessive tissue damage. In someembodiments, the surface of the patient's skin can be cooled to atemperature no lower than about −40° C., −30° C., −20° C., −10° C., −5°C., or −3° C. to produce a partial freeze event in the skin withoutcausing irreversible skin damage. In one example, the surface of theskin can be cooled to from about −40° C. to about 0° C., from about −30°C. to about 0° C., from about −20° C. to about 0° C., or from about −15°C. to about 0° C. or below about −10° C., −20° C., −20° C., −30° C., or−40° C. It will be appreciated that the surface of the skin can becooled to other temperatures that are selected based on the mechanism ofaction.

At block 354, one or more events (e.g., freeze events) can be detectedusing one or more electrical components of the treatment device. Duringcooling, targeted tissue can reach a temperature below the freezingpoint of its biological tissue and fluids (e.g., approximately −1.8°C.). As tissue, fluids, and lipids freeze, crystals can form and energyassociated with the latent heat of crystallization is released. Thetreatment system can determine the extent of freezing based on thedetected temperature changes caused of crystallization. A relativelysmall positive change in tissue temperature can indicate a partial ortotal freeze event whereas a relatively large positive change in tissuetemperature can indicate a complete freeze event. The sensor 167 (FIG.2) and the sensor 227 of FIG. 5 can be freeze detect sensors capable ofdetecting the positive change in tissue temperature, and the treatmentsystem can identify it as a freeze event. The treatment system can beprogrammed so that small temperature variations do not cause falsealarms with respect to false events. Additionally or alternatively, thetreatment systems may detect changes in the temperature of itscomponents or changes in power supplied to treatment devices, or othercomponents, to identify freeze events.

The treatment system 100 of FIG. 3 can use optical techniques to detectcooling events at block 354 of FIG. 7. For example, sensor 167 of FIG. 2and sensors 217, 227 of FIG. 5 can be optical sensors capable ofdetecting changes in the optical characteristics of tissue caused byfreezing. Optical sensors can include, without limitation, one or moreenergy emitters (e.g., light sources, light emitting diodes, etc.),detector elements (e.g., light detectors), or other components fornon-invasively monitoring optical characteristics of tissue. In place ofor in conjunction with monitoring using optical techniques, tissue canbe monitored using electrical and/or mechanical techniques. Inembodiments for measuring electrical impedance of tissue, the sensors(e.g., sensor 167 of FIG. 2 and sensors 217, 227 of FIG. 5) can includetwo electrodes that can be placed in electrical communication with theskin for monitoring electrical energy traveling between the electrodesvia the tissue. In embodiments for measuring mechanical properties oftissue, the sensors disclosed herein can comprise one or more mechanicalsensors which can include, without limitation, force sensors, pressuresensors, and so on.

At block 356, the treatment device and other treatment parameters can becontrolled to control the temperature in the target region and, in someembodiments, includes periodically or continuously cooling the patient'stissue to keep a target region of skin in a cooled state (e.g., a frozenstate) for a period of time. The treatment parameters can include, forexample, cryoprotectant protocols, temperature profiles, treatmentdurations, number of cooling zones, characteristics of cooling zones,energy delivered to tissue, control parameters (e.g., control parametersfor features such as vibration, massage, vacuum, and other treatmentmodes), or the like. For example, the skin within the cooling zone(e.g., event zone 232 of FIG. 5) can be kept frozen for a length of timeselected based on the desired severity of the freeze injury. In shorttreatments, the period of time can be equal to or shorter than about 5,10, 15, 20, or 25 seconds. In longer treatments, the period of time canbe equal to or longer than about 25 seconds, 30 seconds, 45 seconds or1, 2, 3, 4, 5, or 10 minutes. In some procedures, the treatment devicecan be controlled so that the skin is partially or completely frozen forno longer than, for example, 5 minutes, 10 minutes, 20 minutes, 30minutes, 45 minutes, or 1 hour. In some examples, the skin is frozen forabout 1 minute to about 5 minutes, about 5 minutes to about 10 minutes,about 10 minutes to about 20 minutes, about 20 minutes to about 30minutes, or about 30 minutes to about 1 hour.

In some embodiments, the treatment system can control the treatmentdevice so that the freeze event causes apoptotic damage to targetedglands but does not cause such damage to non-targeted tissue. In oneexample, the treatment device produces a partial freeze event shortenough to prevent establishing equilibrium temperature gradients in thepatient's skin. This allows freezing of shallow targeted tissue withoutsubstantially affecting deeper non-targeted tissue. Moreover, cells inthe dermal layer can be affected to a greater extent than the cells inthe subdermal layer (e.g., subcutaneous adipose tissue). In someprocedures, the subdermal layer can be kept at a sufficiently hightemperature (e.g., at or above 0° C.) while the shallower dermal tissueexperiences the partial or total freeze event. The treatment system canalso control operation of the treatment devices to thermally injuretissue to cause fibrosis, which increases the amount of connectivetissue in a desired tissue layer (e.g., epidermis and/or dermis) toincrease the firmness and appearance of the skin. In other treatments,the treatment system controls one or more applicators to supercool andfreeze dermal tissue.

At block 358, the frozen region can be thawed by heating it and/orapplying a topical substance in order to minimize, reduce, or limittissue damage. The applicator can thaw the patient's skin after thefreeze event occurs and after a period of time has transpired. Theperiod of time can be equal to or shorter than about 5, 10, 15, 20, or25 seconds or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes. In oneexample, the uppermost skin layer(s) can be periodically heated to atemperature above the skin's freezing point to provide freeze protectionthereto. The applicator can include one or more thermal elements (e.g.,resistive heaters, electromagnetic energy emitters, Peltier devices,etc.) for heating tissue. For example, a cooling element 109 of FIG. 2can be a Peltier device or one or more resistive heaters capable ofgenerating heat for thawing tissue. In some embodiments, the applicator104 of FIGS. 2 and 3 can have separate and independently controlledcooling elements and heating elements that can cooperate to provideprecise temperature control for freezing and thawing/warming cycles. Insome embodiments, applicators may stop cooling tissue to allow frozentissue to passively warm and thaw.

The treatment systems disclosed herein can monitor the location and/ormovement of the treatment devices and may prevent false or inaccuratedeterminations of treatment events based on such monitoring. Duringtreatment, the treatment device may move which may cause it to contact awarmer area of skin, to no longer contact the skin, and so on. This maycause the treatment system to register a difference in temperature thatis inconsistent with a normal treatment. Controllers (e.g., controller114 of FIG. 3) may be programmed to differentiate between these types oftemperature increases and a temperature increase associated withfreezing. U.S. Pat. No. 8,285,390 discloses techniques for monitoringand detecting freeze events and applicator movement and is incorporatedby reference in its entirety. Additionally, treatment systems canprovide an indication or alarm to alert the operator to the source ofthis temperature increase. In the case of a temperature increase notassociated with an event, the system may also suppress falseindications, while in the case of a temperature increase associated withfreezing, the system take any number of actions based on that detection.

FIG. 8 is a flow diagram illustrating a method 400 in accordance with anaspect of the present technology. Generally, a substance can be appliedto the treatment site. The applicator can be applied to the treatmentsite and can cool tissue while the cryoprotectant protects non-targetedtissue. A cooled region (e.g., a frozen or non-frozen region) can bewarmed (e.g., thawed) to inhibit or limit thermal damage to tissue. Insome embodiments, the treatment site can be monitored to keep tissuefrozen or non-frozen but yet cold for a sufficient length of time toaffect glands. Details of method 400 are discussed below.

At block 402, a substance can be applied to the subject's skin toimprove heat transfer between the treatment device and the subjectsskin, selectively protect non-target tissues from thermal damage (e.g.,freeze damage due to crystallization), and/or initiate/control thermalevents. In one embodiment, the substance can be a cryoprotectant thatprevents, inhibit, or limits damage to non-targeted tissue. Additionallyor alternatively, the cryoprotectant can allow, for example, thetreatment device to be pre-cooled prior to being applied to the subjectfor more efficient treatment. Further, the cryoprotectant can alsoenable the treatment device to be maintained at a desired lowtemperature while preventing ice formation on the cooled surface of thetreatment device, and thus reduces the delay in reapplying the treatmentdevice to the subject. Yet another aspect of the technology is thecryoprotectant may prevent the treatment device from freezing to thesubject's skin. Certain cryoprotectants can allow microscopic crystalsto form in the tissue but can limit crystal growth that would cause celldestruction and, in some embodiments, can allow for enhanced uptake orabsorption and/or retention in target glands and/or surrounding tissueprior to and during cooling.

Some embodiments according to the present technology may use acryoprotectant with a freezing point depressant that can assist inpreventing freeze damage that would destroy cells. Suitablecryoprotectants and processes for implementing cryoprotectants aredescribed in commonly-assigned U.S. Patent Publication No. 2007/0255362.The cryoprotectant may additionally include a thickening agent, a pHbuffer, a humectant, a surfactant, and/or other additives and adjuvantsas described herein. Freezing point depressants may include, forexample, propylene glycol (PG), polyethylene glycol (PEG), dimethylsulfoxide (DMSO), or other suitable alcohol compounds. Cryoprotectantcan be delivered to the surface of the patient's skin for a period oftime which is short enough to not significantly inhibit the initiationof the partial freeze event in dermal tissue but which is long enough toprovide substantial protection to non-targeted tissue epidermal.Multiple cryoprotectants can be used to protect different tissue layers.For example, a first cryoprotectant for protecting deep tissue can beapplied before a second cryoprotectant for protecting shallow tissuebecause the first cryoprotectant may require a longer delivery time toreach the deeper tissue.

The rate of cryoprotectant delivery can be selected based on thecharacteristics of the cryoprotectant and the desired amount of tissueprotection. In one specific treatment, an interface member is placeddirectly over the target area, and the treatment device with adisposable sleeve or liner is placed in contact with the interfacemember. The interface member can be a cotton pad, a gauze pad, a pouch,or a container with a reservoir containing a volume of cryoprotectant orother flowable conductive substance. The interface member can include,for example, a non-woven cotton fabric pad saturated with cryoprotectantthat is delivered at a desired delivery rate. Suitable pads includeWebril™ pads manufactured by Covidien of Mansfield, Mass. Furtherdetails regarding interface members and associated systems and methodsof use are described in commonly-assigned U.S. Patent Publication No.2010/0280582.

In block 404, the subjects skin can be cooled using a treatment devicein thermal contact with the subject's skin. The surface of the subject'sskin can be continuously or periodically cooled to produce a freezeevent (e.g., partial freeze event, complete freeze event, etc.). Thedescription of block 352 in FIG. 7 applies equally to block 404 in FIG.8.

In block 406, thermal energy can be delivered to the surface of the skinbefore, during, and/or after skin cooling to protect non-targeted tissuein the uppermost region of the skin. In some embodiments, the dermaltissue with glands below the epidermis can be frozen/supercooled. Thetreatment device can heat the surface of the skin to warm the epidermisor portions thereof to prevent, inhibit, or limit damage to non-targetedepidermal tissue while the region of dermal tissue with glands remainsin a frozen/supercooled state. If the targeted region is supercooled, itcan be controllably frozen using one or more nucleation initiators(e.g., mechanical perturbation such as vibration, ultrasound pulse,change in pressure, etc.).

Heat can be delivered transcutaneously to the subcutaneous layer toprotect the subcutaneous tissue. For example, subcutaneous tissue can beheated prior to tissue cooling the subject's skin at block 404. In someprocedures, the subcutaneous tissue can be periodically heated (e.g.,heated using radiofrequency energy) during skin cooling. Someembodiments, the skin can be alternatingly heated and cooled. Theheating cycles can be used to keep the subcutaneous tissue at or above athreshold temperature (e.g., above its freezing point) to avoid freezedamage to the subcutaneous layer. The cooling cycles can be used toperiodically cool the targeted dermal tissue and/or epidermal tissue. Insome embodiments, the topical substance can be applied in order tominimize, reduce, or limit tissue damage.

At block 408, the frozen region can be warmed (e.g., thawed). In freezeevent embodiments, the applicator can thaw the patient's skin after thefreeze event occurs and after a period of time has transpired. Thethawing process at block 408 can be the same as the thawing process ofblock 358 of FIG. 7.

E. Treatments using Supercooling

FIGS. 9 and 10 are flow diagrams illustrating methods for supercoolingregions in accordance with embodiments of the technology. Generally, asurface of a human subject's skin can be cooled to a temperature nolower than −40° C. to avoid unwanted skin damage and so that thetemperature of at least a portion of tissue is in a supercooled state.The surface of the skin can be heated to bring shallow non-targetedtissue out of the supercooled state while the deeper targeted regionremains in the supercooled state. The supercooled targeted region can benucleated due to a perturbation that causes at least partial or totalfreezing that destroys or damages targeted cells, for example, due tocrystallization of intracellular and/or extracellular fluids. In oneembodiment, mechanical perturbation and/or other catalyst for nucleation(e.g., RF energy, alternating electric fields, etc.) within the targettissue can be provided only following a protective increase of atemperature of non-targeted epidermal layers. The mechanicalperturbations can be vibrations, ultrasound pulses, and/or changes inpressure. The non-targeted layers can be warmed enough to avoid freezingof non-targeted tissue upon nucleation. The treatment system 100 (FIG.3) can utilize applicators disclosed herein to perform such supercoolingmethods.

FIG. 9 is a flow diagram illustrating a method 450 in accordance with anaspect of the present technology. An early stage of the method 450 caninclude cooling a surface of a human subject's skin to a firsttemperature (block 452). The first temperature can be, for example,between about −10° C. and −40° C. such that a portion of tissue belowthe surface is in a supercooled state. In other embodiments, the firsttemperature can be a temperature between about −15° C. and −25° C., atemperature between about −20° C. and about −30° C., or othertemperature below a freezing temperature.

In block 454, the surface of the human subject's skin is heated anamount sufficient to raise the skin surface temperature from the firsttemperature to a second temperature, which can be a non-supercooledtemperature, while the targeted region remains in the supercooled state.For example, the treatment system can be used to heat the surface of theskin to a temperature higher than about 0° C., higher than about 5° C.,higher than about 10° C., higher than about 20° C., higher than about30° C., or higher than about 35° C. There can be a temperature gradientbetween the targeted tissue and the skin surface such that most of thenon-targeted tissue (e.g., epidermis) is at a non-supercooledtemperature.

In block 456, the supercooled portion of tissue below the skin surfacecan be nucleated to cause at least some fluid and cells in thesupercooled tissue to at least partially or totally freeze. In oneembodiment, nucleation of the supercooled tissue is caused by amechanical perturbation, ultrasound, massaging, or other suitablenucleation initiator. Warmed cells residing at the surface of the humansubject's skin do not freeze at block 456. As such, cells at the skinsurface are protected without using a chemical cryoprotectant. Thechemical cryoprotectants can be selected to inhibit or limithyperpigmentation or hypopigmentation.

In block 458, the supercooled tissue can be maintained in the at leastpartially or totally frozen state for a predetermined period of timelonger than, for example, about 10 seconds, 12 seconds, 15 seconds, or20 seconds. In various arrangements, the supercooled tissue in a coolingzone (e.g., event zone 232 of FIG. 5) can be maintained in the at leastpartially or totally frozen state for a duration of time sufficient totreat acne, improve a quality of hair, treat hyperhidrosis, etc. Incertain embodiments, the skin is cooled/heated to maintain targetedtissue in at least a partially or totally frozen state for thepredetermined time longer than about 10 seconds, longer than about 12seconds, longer than about 15 seconds, or longer than about 20 seconds.

FIG. 10 illustrates a method 500 for affecting a target region in ahuman subject's body in accordance with another embodiment of thepresent technology. The method 500 can include transdermally removingheat from tissue at a target region such that the target region iscooled to a supercooled temperature (block 502). The supercooledtemperature can be, for example, below about 0° C. or within a rangefrom about 0° C. to about −20° C., from about −10° C. to about −30° C.,from about −20° C. to about −40° C., or no lower than about −40° C.Cryoprotectants can be used when cooling tissue to very lowtemperatures, including temperatures lower than −40° C.

In block 504, the method 500 includes applying heat to an epidermis ofthe target region to warm epidermal cells in the target region to atemperature above freezing while glands in the dermis are at or near thesupercooled temperature. For example, the step of applying heat caninclude warming a portion of most of the epidermal layer under thetreatment device to a temperature above about 0° C., about 5° C., about10° C., about 20° C., about 25° C., or about 32° C. Warming can beaccomplished by thermal heaters (e.g., heaters 235 in FIG. 5) disposedon a surface of the applicator contacting or confronting a skin surface.Alternatively, if deeper tissue is not targeted, such tissue could bewarmed using focused electrical currents which focus their energy belowthe skin surface, focused ultrasound which has a focal point for itsenergy below the skin surface, or RF energy. In such embodiments, theelements 235 of FIG. 5 can be electrodes or transducers.

In block 506, a freeze event in the dermal layer can selectively affectthe targeted glands while epidermal cells are not affected by the freezeevent. The method 500 can include providing at least one of vibration,mechanical pressure, and ultrasound pulses to the target region to causesuch a freeze event. In various arrangements, the freeze event can causeat least partial crystallization of a plurality of gland cells in thetarget region. Beneficially, the epidermal cells are protected to avoidor limit freeze damage to those cells.

In some methods 500, supercooled temperatures of the targeted tissue canbe achieved without initiating nucleation by cooling the treatment siteat a relatively slow rate (e.g., the temperature profile can cause aslow cooling of the tissue at the target region) at block 502. Forexample, the rate of cooling can be either equal to, slower or fasterthan about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 degrees C. per minute. Apreferred rate of cooling is about either 2, 4, or 6 degrees C. perminute. Additionally or alternatively, a treatment device can apply agenerally constant pressure during cooling to the supercooledtemperature range to avoid pressure changes that would cause inadvertentnucleation. In a further embodiment, the targeted tissue can be cooledwhile the patient is held still (e.g., without movement of the treatmentsite) to avoid mechanically disturbing the supercooled tissue andunintentionally causing crystallization. At block 504, the temperatureof the non-targeted surface tissue can be warmed to a non-freezingtemperature and/or a non-supercooled temperature prior to perturbationand subsequent freezing. In one embodiment, the warming cycle of thetemperature profile can occur quickly such that the underlying and/ortargeted tissue remains in the supercooled state throughout the warmingcycle. The supercooled tissue can then be nucleated at block 506.

Various aspects of the methods disclosed herein can include cosmetictreatment methods for treating the target region of a human subject'sbody to achieve a cosmetically beneficial alteration of a portion oftissue within the target region. Such cosmetic methods can beadministered by a non-medically trained person. The methods disclosedherein can also be used to (a) improve the appearance of skin bytightening the skin, improving skin tone and texture, eliminating orreducing wrinkles, increasing skin smoothness, thickening the skin, (b)improve the appearance of cellulite, and/or (c) treat sebaceous glands,hair follicles, and/or sweat glands.

F. Suitable Computing Environments

FIG. 11 is a schematic block diagram illustrating subcomponents of acomputing device 700 suitable for the system 100 of FIG. 3 in accordancewith an embodiment of the disclosure. The computing device 700 caninclude a processor 701, a memory 702 (e.g., SRAM, DRAM, flash, or othermemory devices), input/output devices 703, and/or subsystems and othercomponents 704. The computing device 700 can perform any of a widevariety of computing processing, storage, sensing, imaging, and/or otherfunctions. Components of the computing device 700 may be housed in asingle unit or distributed over multiple, interconnected units (e.g.,though a communications network). The components of the computing device700 can accordingly include local and/or remote memory storage devicesand any of a wide variety of computer-readable media.

As illustrated in FIG. 11, the processor 701 can include a plurality offunctional modules 706, such as software modules, for execution by theprocessor 701. The various implementations of source code (i.e., in aconventional programming language) can be stored on a computer-readablestorage medium or can be embodied on a transmission medium in a carrierwave. The modules 706 of the processor can include an input module 708,a database module 710, a process module 712, an output module 714, and,optionally, a display module 716.

In operation, the input module 708 accepts an operator input 719 via theone or more input/output devices described above with respect to FIG. 5,and communicates the accepted information or selections to othercomponents for further processing. The database module 710 organizesrecords, including patient records, treatment data sets, treatmentprofiles and operating records and other operator activities, andfacilitates storing and retrieving of these records to and from a datastorage device (e.g., internal memory 702, an external database, etc.).Any type of database organization can be utilized, including a flat filesystem, hierarchical database, relational database, distributeddatabase, etc.

In the illustrated example, the process module 712 can generate controlvariables based on sensor readings 718 from sensors (e.g., sensor 167 ofFIG. 2, the temperature measurement components 217 and 227 of FIG. 5,etc.) and/or other data sources, and the output module 714 cancommunicate operator input to external computing devices and controlvariables to the controller 114 (FIGS. 3 and 5). The display module 816can be configured to convert and transmit processing parameters, sensorreadings 818, output signals 720, input data, treatment profiles andprescribed operational parameters through one or more connected displaydevices, such as a display screen, printer, speaker system, etc. Asuitable display module 716 may include a video driver that enables thecontroller 114 to display the sensor readings 718 or other status oftreatment progression.

In various embodiments, the processor 701 can be a standard centralprocessing unit or a secure processor. Secure processors can bespecial-purpose processors (e.g., reduced instruction set processor)that can withstand sophisticated attacks that attempt to extract data orprogramming logic. The secure processors may not have debugging pinsthat enable an external debugger to monitor the secure processor'sexecution or registers. In other embodiments, the system may employ asecure field programmable gate array, a smartcard, or other securedevices.

The memory 702 can be standard memory, secure memory, or a combinationof both memory types. By employing a secure processor and/or securememory, the system can ensure that data and instructions are both highlysecure and sensitive operations such as decryption are shielded fromobservation. The memory 702 can contain executable instructions forcooling the surface of the subject's skin to a temperature andcontrolling treatment devices in response to, for example, detection ofa partial or complete freeze events. The memory 702 can include thawinginstructions that, when executed, causes the controller to control theapplicator to heat tissue. In some embodiments, the memory 702 storesinstructions that can be executed to control the applicators to performthe methods disclosed herein without causing undesired effects, such assignificantly lightening or darkening skin one of more days after thefreeze event ends. The instructions can be modified based on patientinformation and treatments to be performed. Other instructions can bestored and executed to perform the methods disclosed herein.

Suitable computing environments and other computing devices and userinterfaces are described in commonly assigned U.S. Pat. No. 8,275,442,entitled “TREATMENT PLANNING SYSTEMS AND METHODS FOR BODY CONTOURINGAPPLICATIONS,” which is incorporated herein in its entirety byreference.

G. CONCLUSION

It will be appreciated that some well-known structures or functions maynot be shown or described in detail, so as to avoid unnecessarilyobscuring the relevant description of the various embodiments. Althoughsome embodiments may be within the scope of the technology, they may notbe described in detail with respect to the Figures. Furthermore,features, structures, or characteristics of various embodiments may becombined in any suitable manner. The technology disclosed herein can beused for improving skin and skin conditions and to perform theprocedures disclosure in U.S. Provisional Application Ser. No.61/943,250, filed Feb. 21, 2014, U.S. Pat. No. 7,367,341 entitled“METHODS AND DEVICES FOR SELECTIVE DISRUPTION OF FATTY TISSUE BYCONTROLLED COOLING” to Anderson et al., and U.S. Patent Publication No.US 2005/0251120 entitled “METHODS AND DEVICES FOR DETECTION AND CONTROLOF SELECTIVE DISRUPTION OF FATTY TISSUE BY CONTROLLED COOLING” toAnderson et al., the disclosures of which are incorporated herein byreference in their entireties. The technology disclosed herein cantarget tissue for tightening the skin, improving skin tone or texture,eliminating or reducing wrinkles, increasing skin smoothness asdisclosed in U.S. Provisional Application Ser. No. 61/943,250.

Unless the context clearly requires otherwise, throughout thedescription, the words “comprise,” “comprising,” and the like are to beconstrued in an inclusive sense as opposed to an exclusive or exhaustivesense; that is to say, in a sense of “including, but not limited to.”Words using the singular or plural number also include the plural orsingular number, respectively. Use of the word “or” in reference to alist of two or more items covers all of the following interpretations ofthe word: any of the items in the list, all of the items in the list,and any combination of the items in the list. In those instances where aconvention analogous to “at least one of A, B, and C, etc.” is used, ingeneral such a construction is intended in the sense of the convention(e.g., “a system having at least one of A, B, and C” would include butnot be limited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and/or A, B, and Ctogether, etc.). In those instances where a convention analogous to “atleast one of A, B, or C, etc.” is used, in general such a constructionis intended in the sense of the convention (e.g., “a system having atleast one of A, B, or C” would include but not be limited to systemsthat have A alone, B alone, C alone, A and B together, A and C together,B and C together, and/or A, B, and C together, etc.).

Any patents, applications and other references, including any that maybe listed in accompanying filing papers, are incorporated herein byreference. Aspects of the described technology can be modified, ifnecessary, to employ the systems, functions, and concepts of the variousreferences described above to provide yet further embodiments. While theabove description details certain embodiments and describes the bestmode contemplated, no matter how detailed, various changes can be made.Implementation details may vary considerably, while still beingencompassed by the technology disclosed herein. The various aspects andembodiments disclosed herein are for purposes of illustration and arenot intended to be limiting, with the true scope and spirit beingindicated by the following claims.

What is claimed is:
 1. A method for treating a subject's exocrineglands, comprising: cooling a surface of a subject's skin with a coolingdevice to produce a freeze event in a portion of the skin with exocrineglands, the surface of the skin being cooled to a temperature higherthan about −40 degrees C.; detecting the freeze event in the patient'sskin; and controlling the cooling device and other treatment parametersto continue to cool the subject's skin after detecting the freeze eventand to maintain at least a partially frozen state of the portion of theskin for a period of time long enough to alter a level of production bythe exocrine glands, the partially frozen state of the portion of theskin is maintained without injuring the epidermis underlying the coolingdevice, and the period of time being longer than about 10 seconds. 2.The method of claim 1, wherein the exocrine glands are sebaceous glandsand/or sweat glands, wherein the cooling device and treatment parametersare controlled so as to not cause either or both hypopigmentation orhyperpigmentation more than a day following the treatment.
 3. The methodof claim 1, wherein the period of time is shorter than about 1 minute, 2minutes, 3 minutes, 4 minutes, 5 minutes, or 10 minutes.
 4. The methodof claim 1, wherein the period of time and temperature are selected sothat lipid rich cells in a subcutaneous layer are not substantiallyaffected by the skin cooling.
 5. The method of claim 1, wherein theperiod of time and temperature are selected so that lipid rich cells ina subcutaneous layer are substantially affected by the skin cooling. 6.The method of claim 1, further comprising thawing the subject's frozenskin after the period of time has transpired to control freeze damagecaused by the skin cooling.
 7. The method of claim 1, further comprisingcontrolling the cooling device so that the freeze event causes moreapoptotic damage to the subject's tissue than necrotic damage.
 8. Themethod of claim 1, further comprising controlling the cooling device andtreatment parameters so that the freeze event causes apoptotic damage tothe subject's glands and does not cause necrotic damage to epidermaland/or subcutaneous tissue.
 9. The method of claim 1, further comprisingcontrolling the cooling device and treatment parameters so that thefreeze event is short enough to prevent equilibrium temperaturegradients from being established in the cooled skin.
 10. The method ofclaim 1, further comprising controlling the cooling device so that thefreeze event begins within a second predetermined period of time afterthe cooling device begins cooling the surface of the skin, the secondpredetermined period of time being shorter than about 30 seconds, orabout 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes.
 11. The method of claim1, wherein the cooling device is controlled to supercool the skin, andfurther comprising heating a surface of the skin to warm an epidermis toa temperature above freezing, then delivering a substance, energy, orpressure to the skin to aid in formation of nucleation sites in thesupercooled skin to initiate the freeze event.
 12. The method of claim1, further comprising delivering a cryoprotectant to the surface of thesubject's skin for a period of time which is short enough to prevent thecryoprotectant from significantly inhibiting initiation of the freezeevent in dermal tissue but is long enough to allow the cryoprotectant toprovide substantial freeze protection to epidermal tissue so as toprevent either hypopigmentation or hyperpigmentation more than a dayfollowing the treatment.
 13. The method of claim 1, wherein the subjectis affected by acne in the portion of the skin with exocrine glands, andwherein the method alters a level of secretion by sebaceous glands inthe portion of the skin, whereby an appearance of the acne is improvedin the portion of the skin.
 14. The method of claim 1, wherein thesubject is affected by hyperhidrosis in the portion of the skin withexocrine glands, and wherein the method alters a level of sweatsecretion by sweat glands in the portion of the skin, wherebyhyperhidrosis is treated in the portion of the skin.
 15. A method fortreating glands of a subject, comprising: cooling a surface of asubject's skin to produce a cooling event at a target region with theglands, the surface of the skin being cooled to a temperature higherthan −40 degrees C.; and controlling a cooling device and othertreatment parameters to cool the surface of the skin for a period oftime and to a temperature sufficiently low to injure the subject'sdermis and the glands therein but without injuring the subject'sepidermis and without injuring the subject's subcutaneous adiposetissue, the period of time being less than about 30 minutes.
 16. Themethod of claim 15, wherein the cooling device and other treatmentparameters are controlled to sufficiently protect an epidermis so as tonot cause either or both hypopigmentation or hyperpigmentation more thana day following the treatment.
 17. The method of claim 15, wherein thetreatment is for treating acne by injuring sebaceous glands.
 18. Themethod of claim 15, wherein the treatment is for treating hyperhidrosisby injuring sweat glands.
 19. The method of claim 15, further comprisingdelivering a cryoprotectant to the skin to protect the subject'sepidermal tissue.
 20. The method of claim 15, further comprisingdelivering thermal energy to the surface of the skin before, during,and/or after skin cooling to protect an uppermost region of the skinfrom freeze damage, and optionally delivering thermal energy to thesubject's subcutaneous tissue transcutaneously through the skin toprotect the subject's subcutaneous layer.
 21. The method of claim 20,further comprising cooling the skin to a supercooled temperature, thenwarming an epidermis to a non-freezing temperature, and then nucleatingthe skin to initiate the freeze event in the supercooled skin.
 22. Themethod of claim 15, further comprising cooling the skin sufficiently toa cause a freeze event, detecting the freeze event, and controlling thecooling device so that the freeze event lasts a second period of timewhich is longer than 10 seconds and shorter than 10 minutes.
 23. Themethod of claim 15, wherein the cooling device is controlled so that amost significant tissue injury cooling zone is centered at a depthbetween about 0.5 mm to about 2.0 mm.
 24. The method of claim 15,wherein the freeze event damages mostly dermal tissue.
 25. The method ofclaim 15, wherein the skin is facial skin or located on either a palm ofa hand, a sole of a foot, brow, scalp, or axilla region.